For the treatment of gastric and esophageal cancers, several pivotal trials—especially those evaluating immune checkpoint inhibitors (ICIs)—have altered the treatment landscape and led to changes in the NCCN Guidelines. In addition to pembrolizumab and nivolumab, new treatment options include trastuzumab-deruxtecan (T-DXd), ramucirumab, and trifluridine/tipiracil. These agents convey varying degrees of benefit depending on treatment line, PD-L1 expression, HER2 expression, and tumor histology. Recently, ICIs have been incorporated into the first-line treatment of HER2-negative advanced esophageal, gastroesophageal junction (GEJ), and gastric cancers, in addition to second-line treatment of advanced esophageal and GEJ cancer of squamous histology. T-DXd is another new second-line option for HER2-positive esophageal, GEJ, and gastric adenocarcinomas. ICIs are now moving into the adjuvant setting as well, and a new recommendation is nivolumab use after preoperative chemoradiation and surgery in patients who have residual disease identified at the time of their R0 resections.
Presenters: Crystal S. Denlinger, Kristina A. Matkowskyj, and Mary F. Mulcahy
Jeremy D. Kratz, Nataliya V. Uboha, Sam J. Lubner, Daniel L. Mulkerin, Linda Clipson, Yanyao Yi, Menggang Yu, Kristina A. Matkowskyj, Noelle K. LoConte, and Dustin A. Deming
Background: Molecular profiles guide the clinical management of metastatic colorectal cancer (mCRC), particularly related to the use of anti–epidermal growth factor receptor (EGFR) antibodies. Tumor sidedness has also been implicated in resistance to these therapies, but has largely been studied in the first-line setting. We examined the role of tumor sidedness and disease bulk in predicting clinical outcomes to anti-EGFR therapy in the treatment-refractory setting. Methods: We identified a retrospective cohort of 62 patients with KRAS wild-type mCRC who received anti-EGFR therapy in the late-line setting. Response was assessed per RECIST 1.1, with bulky disease defined as any single lesion >35 mm in longest cross-sectional diameter or nodal short axis. Primary sidedness was defined in relation to the splenic flexure. Results: Patients with right-sided primary tumors at time of late-line EGFR therapy presented with increased tumor bulk and worsened overall survival (OS) relative to left-sided primary tumors. Tumor bulk, defined as either a categorical or continuous variable, predicted worsened progression-free survival (PFS) and OS, which persisted when controlling for differences in the primary tumor location. Within the right-sided cohort, no objective responses were observed for bulky disease or during treatment with anti-EGFR monotherapy. The nonbulky cohort experienced clinical benefit with anti-EGFR monotherapy, showing similar PFS and an improved response rate compared with sequential chemotherapy. Conclusions: In an effort to expand understanding of the role of primary sidedness in clinical response to anti-EGFR therapy, we identified sidedness and tumor bulk as potential predictive biomarkers of clinical response in late-line mCRC. Future prospective studies of EGFR targeting should consider tumor bulk in addition to molecular profiling in the identification of populations most likely to achieve meaningful clinical benefit.
Jaffer A. Ajani, Thomas A. D’Amico, David J. Bentrem, Joseph Chao, Carlos Corvera, Prajnan Das, Crystal S. Denlinger, Peter C. Enzinger, Paul Fanta, Farhood Farjah, Hans Gerdes, Michael Gibson, Robert E. Glasgow, James A. Hayman, Steven Hochwald, Wayne L. Hofstetter, David H. Ilson, Dawn Jaroszewski, Kimberly L. Johung, Rajesh N. Keswani, Lawrence R. Kleinberg, Stephen Leong, Quan P. Ly, Kristina A. Matkowskyj, Michael McNamara, Mary F. Mulcahy, Ravi K. Paluri, Haeseong Park, Kyle A. Perry, Jose Pimiento, George A. Poultsides, Robert Roses, Vivian E. Strong, Georgia Wiesner, Christopher G. Willett, Cameron D. Wright, Nicole R. McMillian, and Lenora A. Pluchino
Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.